Empagliflozin as a Treatment for Severe Congenital Neutropenia Due to G6PC3 Deficiency

One symptom of G6PC3 deficiency is recurrent infections resulting from severe congenital neutropenia (SCN). Data suggest that SCN is the result of accumulation of the toxic dietary metabolite 1,5 anhydroglucitol 6 phosphate (1,5-AG6P) in leukocytes. This buildup inhibits glycolytic metabolism, thus impairing their function. Increasing urinary glucose excretion results in the urinary excretion of the precursor to 1,5-AG6P, and will likely reduce levels of 1,5-AG6P in leukocytes.

In this phase 1 open-label study, we will evaluate the safety, tolerability, and efficacy of the sodium glucose co transporter 2 inhibitor empagliflozin in patients with G6PC3 deficiency. Empagliflozin is FDA approved in doses of 10 or 25 mg daily for treatment of type 2 diabetes in adults. Eligible participants (n=5) aged >=18 years will be on a 2-month daily regimen of 10 mg of oral empagliflozin (phase A). Participants may then be increased to 25 mg daily (phase B) if the participant fails to achieve an adequate improvement in neutropenia during phase A and is able to tolerate the higher dose, or alternatively may continue on the 10-mg dose. Participants will temporarily discontinue any current granulocyte colony-stimulating factor (G-CSF) regimen starting at least 7 days before the empagliflozin regimen begins, to remove or reduce the effects of concomitant G-CSF so the baseline ANC can be evaluated without confounding factors.

During phase A, participants will have blood drawn locally every two weeks for clinical lab evaluations (including ANC). A member of the study team will also contact the participant for remote AE assessment at each blood draw. During phase B, blood draws and remote AE assessments will be monthly for the first 4 months, and bimonthly for the last 6 months. Participants will have outpatient study visits at the NIH Clinical Center at the end of phase A (month 2), and at months 6 and 12 during phase B.

• INCLUSION CRITERIA:

• Aged >=18 years.
• Documented SCN due to G6PC3 deficiency defined by genetic testing.
• History of ANC consistently <1000 cells/microL when not treated with G-CSF.
• Current ANC<1000 cells/microL when not treated with G-CSF.
• Participants must agree not to become pregnant for the duration of the study. Study participants must use 2 methods of birth control when engaging in sexual activities that can result in pregnancy, beginning 30 days before the first dose of empagliflozin through one month after treatment ends. One method must be a male or female condom. The other method may be any of the following:

• Hormonal contraception.
• Diaphragm or cervical cap with a spermicide.
• Intrauterine device.
• Able to provide informed consent.

Exclusion criteria

Individuals meeting any of the following criteria will be excluded from study participation:

• Renal failure or eGFR<45 mL/min/1.73 m^2.
• Type 1 diabetes mellitus.
• Fasting hypoglycemia (<60 mg/dL).
• Known hypersensitivity or allergy to any component of empagliflozin.
• Pregnant.
• Breastfeeding.
• Any condition that, in the opinion of the investigator, contraindicates participation in this study.